This invention relates to imidazoquinoline compounds that have thioether functionality at the 1-position, and to pharmaceutical compositions containing such compounds. A further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals, and in the treatment of diseases, including viral and neoplastic diseases.
The first reliable report on the 1H-imidazo[4,5-c]quinoline ring system, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H-imidazo[4,5-c]quinolines were reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs. 85, 94362 (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-c]quinolines.
Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of which are incorporated herein by reference.
There continues to be interest in the imidazoquinoline ring system.
Certain 1H-imidazo[4,5-c]naphthyridine-4-amines, 1H-imidazo[4,5-c]pyridin-4-amines, and 1H-imidazo[4,5-c]quinolin-4-amines having an ether containing substituent at the 1 position are known. These are described in U.S. Pat. Nos. 5,268,376; 5,389,640; 5,494,916; and WO 99/29693.
Despite these attempts to identify compounds that are useful as immune response modifiers, there is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.
We have found a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Accordingly, this invention provides imidazoquinoline-4-amine and tetrahydroimidazoquinoline-4-amine compounds that have a thioether containing substituent at the 1-position. The compounds are defined by Formulas (I) and (II), which are defined in more detail infra. These compounds share the general structural formula: 
wherein X, Z, R1, R2, and R are as defined herein for each class of compounds having Formulas (I) and (II).
The compounds of formulas (I) and (II) are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune response when administered to animals. This makes the compounds useful in the treatment of a variety of conditions such as viral diseases and tumors that are responsive to such changes in the immune response.
The invention further provides pharmaceutical compositions containing the immune response modifying compounds, and methods of inducing cytokine biosynthesis in an animal, treating a viral infection in an animal, and/or treating a neoplastic disease in an animal by administering a compound of Formula (I) or (II) to the animal.
In addition, the invention provides methods of synthesizing the compounds of the invention.
As mentioned earlier, we have found certain compounds that induce cytokine biosynthesis and modify the immune response in animals. Such compounds are represented by Formulas (I) and (II) as shown below.
Imidazoquinoline compounds of the invention, which have thioether functionality at the 1-position are represented by Formula (I): 
wherein:
X is xe2x80x94CHR3xe2x80x94, xe2x80x94CHR3-alkyl-, or xe2x80x94CHR3-alkenyl-;
Z is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, or xe2x80x94SO2xe2x80x94;
R1 is selected from the group consisting of:
-alkyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkenyl;
xe2x80x94R4-aryl;
xe2x80x94R4-heteroaryl;
xe2x80x94R4-heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R3)2;
xe2x80x94COxe2x80x94N(R3)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94COxe2x80x94Oxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;
-heteroaryl;
-heterocyclyl;
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
each R3 is independently H or C1-10 alkyl;
R4 is alkyl or alkenyl;
each Y is independently xe2x80x94Oxe2x80x94 or xe2x80x94S(O)0-2xe2x80x94;
n is 0 to 4; and
each R present is independently selected from the group consisting of C1-10 
alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
The invention also includes tetrahydroimidazoquinoline compounds that bear a thioether containing substituent at the 1-position. Such tetrahydroimidazoquinoline compounds are represented by Formula (II): 
wherein:
X is xe2x80x94CHR3xe2x80x94, xe2x80x94CHR3-alkyl-, or xe2x80x94CHR3-alkenyl-;
Z is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, or xe2x80x94SO2xe2x80x94;
R1 is selected from the group consisting of:
-alkyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkenyl;
xe2x80x94R4-aryl;
xe2x80x94R4-heteroaryl; and
xe2x80x94R4-heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R3)2;
xe2x80x94COxe2x80x94N(R3)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94COxe2x80x94Oxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;
-heteroaryl;
-heterocyclyl;
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
each R3 is independently H or C1-10 alkyl;
R4 is alkylene or alkenylene;
Y is xe2x80x94Oxe2x80x94 or xe2x80x94S(O)0-2xe2x80x94;
n is 0 to 4; and
each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof
Preparation of the Compounds
Compounds of the invention can be prepared according to Reaction Scheme I where R, R1, R2, X and n are as defined above.
In step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline of Formula X is reacted with an amine of formula HOxe2x80x94Xxe2x80x94NH2 to provide a 3-nitroquinolin-4-amine of Formula XI. The reaction can be carried out by adding the amine to a solution of a compound of Formula X in a suitable solvent such as chloroform or dichloromethane in the presence of triethylamine and optionally heating. Many quinolines of Formula X are known compounds (see for example, U.S. Pat. No. 4,689,338 and references cited therein). Many amines of formula HOxe2x80x94Xxe2x80x94NH2 are commercially available; others can be readily prepared using known synthetic routes.
In step (2) of Reaction Scheme I a 3-nitroquinolin-4-amine of Formula XI is chlorinated to provide a 3-nitroquinolin-4-amine of Formula XII. Conventional chlorinating agents can be used. Preferably the reaction is carried out by combining a compound of Formula XI with thionyl chloride in a suitable solvent such as dichloromethane. The reaction may be run at ambient temperature or it may be heated. Alternatively the reaction may be run neat.
In step (3) of Reaction Scheme I a 3-nitroquinolin-4-amine of Formula XII is reduced to provide a quinoline-3,4-diamine of Formula XIII. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as toluene.
In step (4) of Reaction Scheme I a quinoline-3,4-diamine of Formula XIII is reacted with a carboxylic acid or an equivalent thereof to provide a 1H-imidazo[4,5-c]quinoline of Formula XIV. Suitable equivalents to a carboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R2 substituent in a compound of Formula XIV. For example, triethyl orthoformate will provide a compound where R2 is hydrogen and trimethyl orthovalerate will provide a compound where R2 is butyl. The reaction can be run in the absence of solvent or in an inert solvent such as toluene. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction. Optionally a catalyst such as pyridine hydrochloride can be included.
Alternatively, step (4) can be carried out by (i) reacting the diamine of Formula XIII with an acyl halide of Formula R2C(O)C1 or R2C(O)Br and then (ii) cyclizing. In part (i) the acyl halide is added to a solution of the diamine in a suitable solvent such as pyridine. The reaction can be carried out at ambient temperature. In part (ii) the product of part (i) is heated in pyridine in the presence of pyridine hydrochloride.
In step (5) of Reaction Scheme I a 1H-imidazo[4,5-c]quinoline of Formula XIV is oxidized to provide a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XV using a conventional oxidizing agent capable of forming N-oxides. Preferably a solution of a compound of Formula XIV in a suitable solvent such as chloroform or dichloromethane is treated with 3-chloroperoxybenzoic acid at ambient temperature.
In step (6) of Reaction Scheme I a 1H-imidazo[4,5-c]quinoline-5N-oxide of Formula XV is aminated to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XVI. Step (6) involves (i) reacting a compound of Formula XV with an acylating agent and then (ii) reacting the product with an aminating agent. Part (i) of step (6) involves reacting an N-oxide of Formula XV with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chlorides (e.g., benezenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred. Para-toluenesulfonyl chloride is most preferred. Part (ii) of step (6) involves reacting the product of part (i) with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is preferred. The reaction is preferably carried out by dissolving the N-oxide of Formula XV in an inert solvent such as dichloromethane or chloroform, adding the aminating agent to the solution, and then slowly adding the acylating agent.
In step (7) of Reaction Scheme I a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XVI is reacted with a compound of Formula R1xe2x80x94SNa to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII which is a subgenus of Formula I. The reaction can be carried out by combining a compound of Formula XVI with a compound of formula R1SNa in a suitable solvent such as N,N-dimethylformamide or dimethyl sulfoxide. The reaction may be run at ambient temperature or it may be heated (60-80xc2x0 C.). The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (8) of Reaction Scheme I a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XVII is oxidized using a conventional oxidizing agent to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XVIII which is a subgenus of Formula I. Preferably a solution of a compound of Formula XVII in a suitable solvent such as chloroform or dichloromethane is treated with 3-chloroperoxybenzoic acid at ambient temperature. The degree of oxidation is controlled by adjusting the amount of 3-chloroperoxybenzoic acid used in the reaction; i.e., using approximately one equivalent will provide the sulfoxide whereas using two equivalents will provide the sulfone. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
Compounds of the invention can be prepared according to Reaction Scheme II where R, R1, R2, X and n are as defined above.
In step (1) of Reaction Scheme II a 3-nitroquinolin-4-amine of Formula XII is reacted with a compound of the Formula R1xe2x80x94SNa using the method of step (7) of Reaction Scheme I to provide a 3-nitroquinolin-4-amine of Formula XIX.
In step (2) of Reaction Scheme II a 3-nitroquinolin-4-amine of Formula XIX is reduced using the method of step (3) of Reaction Scheme I to provide a quinoline-3,4-diamine of Formula XX.
In step (3) of Reaction Scheme II a quinoline-3,4-diamine of Formula XX is cyclized using the method of step (4) of Reaction Scheme I to provide a 1H-imidazo[4,5-c]quinoline of Formula XXI.
In step (4) of Reaction Scheme II a 1H-imidazo[4,5-c]quinoline of Formula XXI is oxidized to provide a 1H-imidazo[4,5-c]quinolin-5N-oxide of Formula XXII using a conventional oxidizing agent. Preferably a solution of a compound of Formula XXI in a suitable solvent such as chloroform or dichloromethane is treated with at least three equivalents of 3-chloroperoxybenzoic acid at ambient temperature.
In step (5) of Reaction Scheme II a 1H-imidazo[4,5-c]quinolin-5N-oxide of Formula XXII is aminated using the method of step (6) of Reaction Scheme I to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XVIII which is a subgenus of Formula I. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
Compounds of the invention can be prepared according to Reaction Scheme III where R, R1, R2, X and n are as defined above.
In step (1) of Reaction Scheme III a 3-nitro-4-amino-quinolin-1-yl alcohol of Formula XI is protected with a tert-butyldimethylsilyl group using conventional methods. Preferably a compound of Formula XI is combined with tert-butyldimethylsilyl chloride in a suitable solvent such as chloroform in the presence of triethylamine and a catalytic amount of 4-dimethylaminopyridine.
In step (2) of Reaction Scheme III a protected 3-nitro-4-amino-quinolin-1-yl alcohol of Formula XXIII is reduced using the method of step (3) of Reaction Scheme I to provide a protected 3, 4-diamino-quinolin-1-yl alcohol of Formula XXIV.
In step (3) of Reaction Scheme III a protected 3,4-diamino-quinolin-1-yl alcohol of Formula XXIV is cyclized using the method of step (4) of Reaction Scheme I to provide a 1H-imidazo[4,5-c]quinoline of Formula XXV.
In step (4) of Reaction Scheme III a 1H-imidazo[4,5-c]quinoline of Formula XXV is oxidized using the method of step (5) of Reaction Scheme I to provide a 1H-imidazo[4,5-c]quinolin-5N-oxide of Formula XXVI.
In step (5) of Reaction Scheme III a 1H-imidazo[4,5-c]quinolin-5N-oxide of Formula XXVI is aminated using the method of step (6) of Reaction Scheme I to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXVII.
In step (6) of Reaction Scheme III the protecting group is removed from a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXVII to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXVIII. Preferably a solution of a compound of Formula XXVII in a suitable solvent such as tetrahydrofuran is treated with tetrabutylammonium fluoride. Some compounds of Formula XXVIII are known, see for example, Gerster, U.S. Pat. No. 4,689,338 and Gerster et al., U.S. Pat. No. 5,605,899.
In step (7) of Reaction Scheme III a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXVIII is chlorinated using conventional methods to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XVI. A compound of Formula XXVIII can be heated neat with thionyl chloride. Alternatively, phosphorous oxychloride can be added in a controlled fashion to a solution of a compound of Formula XXVIII in a suitable solvent such as N,N-dimethylformamide in the presence of triethylamine.
Steps (8) and (9) of Reaction Scheme III can be carried out in the same manner as steps (7) and (8), respectively, of Reaction Scheme I. 
Compounds of the invention can be prepared according to Reaction Scheme IV where R, R1, R2, X and n are as defined above and BOC is tert-butoxycarbonyl.
In step (1) of Reaction Scheme IV the hydroxy group of a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XXIX is protected with a tert-butyldimethylsilyl group using the method of step (1) of Reaction Scheme III. Compounds of Formula XXIX are known or can be prepared using known synthetic methods, see for example, Nikolaides, et al., U.S. Pat. No. 5,352,784 and Lindstrom, U.S. Pat. No. 5,693,811 and references cited therein.
In step (2) of Reaction Scheme IV the amino group of a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXX is protected using conventional methods to provide a protected 1H-imidazo[4,5-c]quinoline of Formula XXXI. Preferably a compound of Formula XXX is treated with di-tert-butyl dicarbonate in a suitable solvent such as tetrahydrofuran in the presence of triethylamine and 4-dimethylaminopyridine. The reaction can be run at an elevated temperature (60xc2x0 C.).
In step (3) of Reaction Scheme IV the tert-butyldimethylsilyl protecting group of a compound of Formula XXXI is removed using the method of step (6) of Reaction Scheme III to provide a 1H-imidazo[4,5-c]quinolin-1yl alcohol of Formula XXXII.
In step (4) of Reaction Scheme IV a 1H-imidazo[4,5-c]quinolin-1yl alcohol of Formula XXXII is converted to a methanesulfonate of Formula XXXIII. Preferably a solution of a compound of Formula XXXII in a suitable solvent such as dichloromethane is treated with methanesulfonyl chloride in the presence of triethylamine. The reaction can be run at a reduced temperature (xe2x88x9210xc2x0 C.).
In step (5) of Reaction Scheme IV a methanesulfonate of Formula XXXIII is reacted with a thiol of formula R1SH to provide a thioether of Formula XXXIV. Preferably a solution of a compound of Formula XXXIII in a suitable solvent such as N, N-dimethylformamide is treated with the thiol in the presence of triethylamine. The reaction can be run at an elevated temperature (80xc2x0 C.).
In step (6) of Reaction Scheme IV the tert-butoxycarbonyl protecting groups are removed by hydrolysis under acidic conditions to provide a 1H-imidazo[4,5-c]quinolin-4-amine of Formula XXXV which is a subgenus of Formula II. Preferably a solution of a compound of Formula XXXIV in a suitable solvent such as dichloromethane is treated at ambient temperature with a solution of hydrochloric acid in dioxane. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (7) of Reaction Scheme IV a thioether of Formula XXXV is oxidized using the method of step (8) of Reaction Scheme I to provide a sulfone or sulfoxide of Formula XXXVI which is a subgenus of Formula II. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
Compounds of the invention can be prepared according to Reaction Scheme V where R, R1, R2, X and n are as defined above.
In step (1) of Reaction Scheme V a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl alcohol of Formula XXIX is chlorinated using the method of step (7) of Reaction Scheme III to provide a compound of Formula XXXVII.
In step (2) of Reaction Scheme V a compound of Formula XXXVII is reacted with a compound of formula R1xe2x80x94SNa using the method of step (7) of Reaction Scheme I to provide a thioether of Formula XXXV which is a subgenus of Formula II. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (3) of Reaction Scheme V a thioether of Formula XXXV is oxidized using the method of step (8) of Reaction Scheme I to provide a sulfone or sulfoxide of Formula XXXVI which is a subgenus of Formula II. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
Compounds of the invention can be prepared according to Reaction Scheme VI where R, R1, R2, X, Z and n are as defined above.
In Reaction Scheme VI a 1H-imidazo[4,5-c]quinoline of Formula I is reduced to provide a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula II. The reduction is carried out by dissolving a compound of Formula I in trifluoroacetic acid, adding a catalytic amount of platinum (IV) oxide, then subjecting the mixture to hydrogen pressure. The reaction can conveniently be carried out on a Parr apparatus. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
Compounds of the invention can be prepared according to Reaction Scheme VII where R, R1, R2, X and n are as defined above and Ph is phenyl.
In step (1) of Reaction Scheme VII a 2,4-dihydroxy-3-nitro-6,7,8,9-tetrahydroquinoline of Formula XXXVIII is chlorinated using conventional chlorinating agents to provide a 2,4-dichloro-3-nitro-6,7,8,9-tetrahydroquinoline of Formula XXXIX. Preferably a compound of Formula XXXVIII is combined with phosphorous oxychloride and heated. Some 2,4-dihydroxy-3-nitro-6,7,8,9-tetrahydroquinolines of Formula XXXVIII are known and others can be prepared using known synthetic methods, see for example, Nikolaides et al., U.S. Pat. No. 5,352,784 and the references cited therein.
In step (2) of Reaction Scheme VII, a 2,4-dichloro-3-nitro-6,7,8,9-tetrahydroquinoline of Formula XXXIX is reacted with an amine of formula HOxe2x80x94Xxe2x80x94NH2 to provide a 2-chloro-3-nitro-6,7,8,9-tetrahydroquinoline of Formula XXXX. The reaction can be carried out by adding the amine to a solution of a compound of Formula XXXIX in a suitable solvent such as N,N-dimethylformamide in the presence of triethylamine and optionally heating.
In step (3) of Reaction Scheme VII, a 2-chloro-3-nitro-6,7,8,9-tetrahydroquinoline of Formula XXXX is reacted with sodium phenoxide to provide a 3-nitro-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXI. Phenol is reacted with sodium hydride in a suitable solvent such as 1,2-dimethoxyethane to form the phenoxide. The phenoxide is then reacted at an elevated temperature with a compound of Formula XXXX.
In step (4) of Reaction Scheme VII, a 3-nitro-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXI is chlorinated using conventional chlorinating agents to provide a 3-nitro-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXII. Preferably N-chlorosuccinimide is reacted with triphenylphosphine in a suitable solvent such as tetrahydrofuran to form the phosphino chloride, which is then reacted with a compound of Formula XXXXI.
In Step (5) of Reaction Scheme VII, a 3-nitro-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXII is reduced using conventional methods to provide a 3-amino-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXIII. A preferred method involves the in situ generation of Ni2B. Sodium borohydride is added to a mixture of nickel(II)chloride hexahydrate and a compound of Formula XXXXII in 50/50 methanol/chloroform.
In step (6) of Reaction Scheme VII, a 3-amino-2-phenoxy-6,7,8,9-tetrahydroquinoline of Formula XXXXIII is cyclized using the method of step (4) of Reaction Scheme I to provide a 4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula III.
In step (7) of Reaction Scheme VII, a 4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula III is reacted with a compound of Formula R1SNa to provide a 4-phenoxy-6,7,8,9-tetrahydro-6,7,8,9-1H-imidazo[4,5-c]quinoline of Formula XXXXIV which is a subgenus of Formula IV. Preferably a thiol of the Formula R1SH is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to generate the anion, which is then reacted with a compound of Formula III.
In step (8a) of Reaction Scheme VII, 4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula XXXXIV is aminated to provide a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-4-amine of Formula XXXV which is a subgenus of Formula II. The reaction can be carried out by combining a compound of Formula XXXXIV with ammonium acetate and heating (xcx9c150xc2x0 C.). Optionally, the reaction may be carried out in a pressure vessel. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (8b) of Reaction Scheme VII, a 4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula XXXXIV is oxidized using the method of step (8) of Reaction Scheme I to provide a 4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula XXXXV which is a subgenus of Formula IV.
In step (9) of Reaction Scheme VII, a 4-phenoxy-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline of Formula XXXXV is aminated using the method of step (8a) to provide a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-4-amine of Formula XXXVI which is a subgenus of Formula II. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. 
The invention also provides novel compounds useful as intermediates in the synthesis of compounds of Formula II. These intermediates have structural Formulas III and IV described in more detail below.
One class of intermediate compounds has the Formula III: 
wherein:
X is xe2x80x94CHR3xe2x80x94, xe2x80x94CHR3-alkyl-, or xe2x80x94CHR3-alkenyl-;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R3)2;
xe2x80x94COxe2x80x94N(R3)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94COxe2x80x94Oxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;
-heteroaryl;
-heterocyclyl;
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
each R3 is independently H or C1-10 alkyl;
Y is xe2x80x94Oxe2x80x94 or xe2x80x94S(O)0-2xe2x80x94;
n is 0 to 4; and
each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Another class of intermediates has the Formula IV: 
wherein:
X is xe2x80x94CHR3xe2x80x94, xe2x80x94CHR3-alkyl-, or xe2x80x94CHR3-alkenyl-;
Z is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, or xe2x80x94SO2xe2x80x94;
R1 is selected from the group consisting of:
-alkyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkenyl;
xe2x80x94R4-aryl;
xe2x80x94R4-heteroaryl; and
xe2x80x94R4-heterocyclyl;
R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl;
-alkyl-Y-alkenyl;
-alkyl-Y-aryl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
xe2x80x94OH;
-halogen;
xe2x80x94N(R3)2;
xe2x80x94COxe2x80x94N(R3)2;
xe2x80x94COxe2x80x94C1-10 alkyl;
xe2x80x94COxe2x80x94Oxe2x80x94C1-10 alkyl;
xe2x80x94N3;
-aryl;
-heteroaryl;
-heterocyclyl;
xe2x80x94CO-aryl; and
xe2x80x94CO-heteroaryl;
each R3 is independently H or C1-10 alkyl;
R4 is alkylene or alkenylene;
Y is xe2x80x94Oxe2x80x94 or xe2x80x94S(O)0-2xe2x80x94;
n is 0 to 4; and
each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
As used herein, the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and the prefix xe2x80x9calk-xe2x80x9d are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms. Preferred groups have a total of up to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl and adamantyl.
In addition, the alkyl and alkenyl portions of-Xxe2x80x94 groups can be unsubstituted or substituted by one or more substituents, which substituents are selected from the groups consisting of alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl.
The term xe2x80x9chaloalkylxe2x80x9d is inclusive of groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of groups that include the prefix xe2x80x9chalo-xe2x80x9d. Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
The term xe2x80x9carylxe2x80x9d as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The term xe2x80x9cheteroarylxe2x80x9d includes aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and so on.
xe2x80x9cHeterocyclylxe2x80x9d includes non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups. Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, and the like.
The aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy, arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylaminocarbonylamino, heteroarylalkylcarbonylamino, and, in the case of heterocyclyl, oxo. If any other groups are identified as being xe2x80x9csubstitutedxe2x80x9d or xe2x80x9coptionally substitutedxe2x80x9d, then those groups can also be substituted by one or more of the above enumerated substituents.
Certain substituents are generally preferred. For example, preferred X groups include ethylene and n-butylene and preferred R1 groups are alkyl and aryl, with phenyl or substituted phenyl a preferred aryl group. Preferably no R substituents are present (i.e., n is 0). Preferred R2 groups include hydrogen, alkyl groups having 1 to 4 carbon atoms (i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and cyclopropylmethyl), methoxyethyl, and ethoxymethyl. One or more of these preferred substituents, if present, can be present in the compounds of the invention in any combination.
The invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, and the like. In particular, if a compound is optically active, the invention specifically includes each of the compound""s enantiomers as well as racemic mixtures of the enantiomers.
Pharmaceutical Compositions and Biological Activity
Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier.
The term xe2x80x9ca therapeutically effective amountxe2x80x9d means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction, antitumor activity, and/or antiviral activity. Although the exact amount of active compound used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound, the nature of the carrier, and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 xcexcg/kg to about 5 mg/kg, of the compound to the subject. Any of the conventional dosage forms may be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
The compounds of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, etc.
The compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
Cytokines whose production may be induced by the administration of compounds according to the invention generally include interferon-xcex1 (IFN-xcex1) and/or tumor necrosis factor-xcex1 (TNF-xcex1) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds of the invention include IFN-xcex1, TNF-xcex1, IL-1, IL-6, L-10 and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and tumors. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
Certain compounds of the invention have been found to preferentially induce the expression of IFN-xcex1 in a population of hematopoietic cells such as PBMCs (peripheral blood mononuclear cells) containing pDC2 cells (precursor dendritic cell-type 2) without concomitant production of significant levels of inflammatory cytokines.
In addition to the ability to induce the production of cytokines, the compounds of the invention affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction. The compounds may also activate macrophages, which in turn stimulates secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes.
Compounds of the invention also have an effect on the acquired immune response. For example, although there is not believed to be any direct effect on T cells or direct induction of T cell cytokines, the production of the T helper type 1 (Th1) cytokine IFN-xcex3 is induced indirectly and the production of the T helper type 2 (Th2) cytokines IL-4, IL-5 and IL-13 are inhibited upon administration of the compounds. This activity means that the compounds are useful in the treatment of diseases where upregulation of the Th1 response and/or downregulation of the Th2 response is desired. In view of the ability of compounds of the invention to inhibit the Th2 immune response, the compounds are expected to be useful in the treatment of atopic diseases, e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
The immune response modifying effects of the compounds make them useful in the treatment of a wide variety of conditions. Because of their ability to induce the production of cytokines such as IFN-xcex1 and/or TNF-xcex1, the compounds are particularly useful in the treatment of viral diseases and tumors. This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such as, but not limited to, viral diseases including genital warts; common warts; plantar warts; Hepatitis B; Hepatitis C; Herpes Simplex Virus Type I and Type II; molluscum contagiosum; variola, particularly variola major; HIV; CMV; VZV; rhinovirus; adenovirus; influenza; and para-influenza; intraepithelial neoplasias such as cervical intraepithelial neoplasia; human papillomavirus (HPV) and associated neoplasias; fungal diseases, e.g. candida, aspergillus, and cryptococcal meningitis; neoplastic diseases, e.g., basal cell carcinoma, hairy cell leukemia, Kaposi""s sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin""s lymphoma, cutaneous T-cell lymphoma, and other cancers; parasitic diseases, e.g. pneumocystis camii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, and leishmaniasis; and bacterial infections, e.g., tuberculosis, and mycobacterium avium. Additional diseases or conditions that can be treated using the compounds of the invention include actinic keratosis; eczema; eosinophilia; essential thrombocythaemia; leprosy; multiple sclerosis; Ommen""s syndrome; discoid lupus; Bowen""s disease; Bowenoid papulosis; alopecia areata; the inhibition of Keloid formation after surgery and other types of post-surgical scars. In addition, these compounds could enhance or stimulate the healing of wounds, including chronic wounds. The compounds may be useful for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV patients.
An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN-xcex1, TNF-xcex1, IL-1, IL-6, IL-10 and IL-12 that is increased over the background level of such cytokines. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 xcexcg/kg to about 5 mg/kg. The invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or composition of the invention to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 xcexcg/kg to about 5 mg/kg. An amount of a compound effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 xcexcg/kg to about 5 mg/kg.
The invention is further described by the following examples, which are provided for illustration only and are not intended to be limiting in any way.